{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:04:09Z","timestamp":1772168649305,"version":"3.50.1"},"reference-count":25,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":33,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"crossref","award":["R01DC012564"],"award-info":[{"award-number":["R01DC012564"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"crossref","award":["R01DC019054"],"award-info":[{"award-number":["R01DC019054"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MC_U142684175"],"award-info":[{"award-number":["MC_U142684175"]}]},{"name":"Medical Research Council","award":["MR\/X004597\/1"],"award-info":[{"award-number":["MR\/X004597\/1"]}]},{"name":"Medical Research Council","award":["MC_UP_1503\/2"],"award-info":[{"award-number":["MC_UP_1503\/2"]}]},{"DOI":"10.13039\/100008510","name":"University of Maryland","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008510","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Humans and mice with mutations in genes encoding CIB2 and whirlin (WHRN) are deaf. We previously reported that CIB2 binds to WHRN and is essential for stereocilia staircase architecture of cochlear hair cells. Here, we refine the interaction domains of both proteins and show that these proteins play unique roles in stereocilia bundle formation and organization. We found that the EF2 domain of CIB2 binds to the HHD2 region of WHRN. AlphaFold2 multimer independently identified the same interacting regions and gave a thorough structural model. Next, we investigated genetic interaction between murine Cib2 and Whrn. Hearing in mice double heterozygous for functionally null alleles (Cib2KO\/+;Whrnwi\/+) was similar to that in age-matched wild-type mice, indicating that partial deficiency for both Cib2 and Whrn does not impair hearing. Double homozygous mutant mice (Cib2KO\/KO;Whrnwi\/wi) were deaf, and their cochlear stereocilia exhibited a predominant phenotype seen in single Whrnwi\/wi mutants. Overexpression of WHRN in Cib2KO\/KO mice did not rescue the stereocilia morphology. These data suggest that CIB2 is multifunctional, with key independent functions in the development and\/or maintenance of the stereocilia staircase pattern in auditory hair cells.<\/jats:p>","DOI":"10.1242\/dmm.052043","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T04:27:09Z","timestamp":1741926429000},"source":"Crossref","is-referenced-by-count":1,"title":["CIB2 function is distinct from that of whirlin in the organization of sterocilia architecture"],"prefix":"10.1242","volume":"18","author":[{"given":"Arnaud P. J.","family":"Giese","sequence":"first","affiliation":[{"name":"University of Maryland School of Medicine 1 Department of Otorhinolaryngology \u2013 Head and Neck Surgery , , Baltimore, MD 21201 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Parker","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]},{"name":"Harwell Campus 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sakina","family":"Rehman","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine 1 Department of Otorhinolaryngology \u2013 Head and Neck Surgery , , Baltimore, MD 21201 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve D. M.","family":"Brown","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]},{"name":"Harwell Campus 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saima","family":"Riazuddin","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine 1 Department of Otorhinolaryngology \u2013 Head and Neck Surgery , , Baltimore, MD 21201 ,","place":["USA"]},{"name":"University of Maryland School of Medicine 3 Department of Biochemistry and Molecular Biology , , Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig W.","family":"Vander Kooi","sequence":"additional","affiliation":[{"name":"University of Florida 4 Department of Biochemistry and Molecular Biology , , Gainesville, FL 32603 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Bowl","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]},{"name":"Harwell Campus 2 , Mammalian Genetics Unit , , Oxfordshire OX11 0RD ,","place":["UK"]},{"name":"UCL Ear Institute, University College London 5 , London WC1X 8EE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2914-4502","authenticated-orcid":false,"given":"Zubair M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine 1 Department of Otorhinolaryngology \u2013 Head and Neck Surgery , , Baltimore, MD 21201 ,","place":["USA"]},{"name":"University of Maryland School of Medicine 3 Department of Biochemistry and Molecular Biology , , Baltimore, MD 21205 ,","place":["USA"]},{"name":"University of Maryland School of Medicine 6 Department of Ophthalmology and Visual Sciences , , Baltimore, MD 21201 ,","place":["USA"]},{"name":"University of Maryland 7 Program in Neuroscience and Cognitive Science , , College Park, MD 20742 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"2025040308352654700_DMM052043C1","doi-asserted-by":"publisher","first-page":"13958","DOI":"10.1073\/pnas.2334417100","article-title":"Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle","volume":"100","author":"Belyantseva","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025040308352654700_DMM052043C2","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/ncb1219","article-title":"Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia","volume":"7","author":"Belyantseva","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"2025040308352654700_DMM052043C3","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1091\/mbc.E16-08-0583","article-title":"Harnessing molecular motors for nanoscale pulldown in live cells","volume":"28","author":"Bird","year":"2017","journal-title":"Mol. Biol. Cell"},{"key":"2025040308352654700_DMM052043C4","doi-asserted-by":"publisher","first-page":"10833","DOI":"10.1038\/ncomms10833","article-title":"Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like","volume":"7","author":"Ebrahim","year":"2016","journal-title":"Nat. Commun."},{"key":"2025040308352654700_DMM052043C5","article-title":"Protein complex prediction with AlphaFold-Multimer","author":"Evans","year":"2021","journal-title":"bioRxiv"},{"key":"2025040308352654700_DMM052043C6","doi-asserted-by":"publisher","first-page":"13898","DOI":"10.1073\/pnas.1304644110","article-title":"Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2","volume":"110","author":"Furness","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025040308352654700_DMM052043C7","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41467-017-00061-1","article-title":"CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells","volume":"8","author":"Giese","year":"2017","journal-title":"Nat. Commun."},{"key":"2025040308352654700_DMM052043C8","doi-asserted-by":"publisher","first-page":"e89719","DOI":"10.7554\/eLife.89719","article-title":"Complexes of vertebrate TMC1\/2 and CIB2\/3 proteins form hair-cell mechanotransduction cation channels","volume":"12","author":"Giese","year":"2025","journal-title":"eLife"},{"key":"2025040308352654700_DMM052043C9","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1002\/cne.10301","article-title":"Elongation of hair cell stereocilia is defective in the mouse mutant whirler","volume":"450","author":"Holme","year":"2002","journal-title":"J. Comp. Neurol."},{"key":"2025040308352654700_DMM052043C10","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2025040308352654700_DMM052043C11","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cub.2019.11.076","article-title":"Mechanotransduction-dependent control of stereocilia dimensions and row identity in inner hair cells","volume":"30","author":"Krey","year":"2020","journal-title":"Curr. Biol."},{"key":"2025040308352654700_DMM052043C12","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.jmb.2007.05.022","article-title":"Inference of macromolecular assemblies from crystalline state","volume":"372","author":"Krissinel","year":"2007","journal-title":"J. Mol. Biol."},{"key":"2025040308352654700_DMM052043C13","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1016\/j.neuron.2021.05.007","article-title":"CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells","volume":"109","author":"Liang","year":"2021","journal-title":"Neuron"},{"key":"2025040308352654700_DMM052043C14","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cub.2010.12.046","article-title":"Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8","volume":"21","author":"Manor","year":"2011","journal-title":"Curr. Biol."},{"key":"2025040308352654700_DMM052043C15","doi-asserted-by":"publisher","first-page":"14907","DOI":"10.1038\/ncomms14907","article-title":"Defective Gpsm2\/Galpha(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome","volume":"8","author":"Mauriac","year":"2017","journal-title":"Nat. Commun."},{"key":"2025040308352654700_DMM052043C16","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/ng1208.ng1208","article-title":"Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31","volume":"34","author":"Mburu","year":"2003","journal-title":"Nat. Genet."},{"key":"2025040308352654700_DMM052043C17","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.15252\/emmm.201708087","article-title":"CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival","volume":"9","author":"Michel","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"2025040308352654700_DMM052043C18","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/ng.2426","article-title":"Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48","volume":"44","author":"Riazuddin","year":"2012","journal-title":"Nat. Genet."},{"key":"2025040308352654700_DMM052043C19","doi-asserted-by":"publisher","first-page":"3906","DOI":"10.1038\/s41467-021-24056-1","article-title":"CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function","volume":"12","author":"Sethna","year":"2021","journal-title":"Nat. Commun."},{"key":"2025040308352654700_DMM052043C20","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/j.cub.2019.01.051","article-title":"GPSM2-GNAI specifies the tallest stereocilia and defines hair bundle row identity","volume":"29","author":"Tadenev","year":"2019","journal-title":"Curr. Biol."},{"key":"2025040308352654700_DMM052043C21","doi-asserted-by":"publisher","first-page":"3926","DOI":"10.1242\/dev.139089","article-title":"A link between planar polarity and staircase-like bundle architecture in hair cells","volume":"143","author":"Tarchini","year":"2016","journal-title":"Development"},{"key":"2025040308352654700_DMM052043C22","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"2025040308352654700_DMM052043C23","doi-asserted-by":"publisher","first-page":"e24661","DOI":"10.7554\/eLife.24661","article-title":"Mechanotransduction current is essential for stability of the transducing stereocilia in mammalian auditory hair cells","volume":"6","author":"Velez-Ortega","year":"2017","journal-title":"eLife"},{"key":"2025040308352654700_DMM052043C24","doi-asserted-by":"publisher","first-page":"401","DOI":"10.3389\/fnmol.2017.00401","article-title":"Loss of CIB2 causes profound hearing loss and abolishes mechanoelectrical transduction in mice","volume":"10","author":"Wang","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"2025040308352654700_DMM052043C25","doi-asserted-by":"publisher","first-page":"e1001048","DOI":"10.1371\/journal.pbio.1001048","article-title":"Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells","volume":"9","author":"Zampini","year":"2011","journal-title":"PLoS Biol."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052043\/3639239\/dmm052043.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052043\/3642944\/dmm052043.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052043\/3642944\/dmm052043.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T08:35:38Z","timestamp":1743669338000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/18\/3\/dmm052043\/367581\/CIB2-function-is-distinct-from-that-of-whirlin-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,1]]},"references-count":25,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.052043","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.07.30.605852","asserted-by":"object"}]},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,1]]},"article-number":"dmm052043"}}